The project will focus on the pathophysiology of the calcific degeneration of bioprosthetic heart valves as an experimental model of a typical cardiovascular calcification. The working hypothesis of this program will be that local administration of diphosphonate compounds directly into the bioprosthetic valve cusp can inhibit the pathogenesis of cuspal calcification at a lower total body dosage than required systemically, while avoiding the generalized adverse effects of systemically administered diphosphonates. Thus, we propose investigations of: the threshold of diphosphonate administration required for an inhibitory effect and the associated localized mineralization events; identification of critical periods and the associated developmental stage of the pathologic calcification in which there can be effective intervention to inhibit calcification; the duration of diphosphonate therapy required for long-term inhibition of the pathogenesis of the calcification process; and the effects of blood-material interactions and dynamic stress on the pathophysiology of this disease process and its therapy. The principal experimental approach in this program will involve bioprosthetic heart valve implants, employing both subcutaneous cuspal implants in rats as well as circulatory implants in sheep and calves with local diphosphonate therapy administered with controlled-release, polymer-based implantable matrices, delivering drug by direct diffusion into the cuspal implant. The specific aims of this research program are as follows: (1) To formulate and study the drug release characteristics of implantable polymer-based controlled-release matrices. (2) To study the pathophysiology and therapy of bioprosthetic heart valve implant calcification in the presence of local targetted diphosphonate therapy.